Approximately 15 percent of patients recover from hepatitis C virus (HCV) infection while 85 percent become persistently infected with various degrees of associated chronic liver disease. In this study, comparisons will be made between patients who rapidly recover, those who have delayed recovery, those with persistent infection and stable chronic disease and those with rapidly progressive, fatal infection. The parameters measured will be viral burden (initially and over time), HCV genotype, the number of viral quasi-species (extent of viral heterogeneity) at the time of infection and subsequently, neutralizing antibody responses and, T-cell helper, proliferative and cytotoxic responses. The goal is to determine if any of these parameters can predict outcome. Studies to date have shown no correlation with genotype since the population is fairly homogeneous for HCV genotype 1. However, there does appear to be a correlation between viral quasi-species and disease outcome. Using rare specimens obtained during the first 16 weeks of HCV infection, we have measured the mean Hamming distance that reflects the extent of viral diversity (the degree of sequence divergence within the viral quasi-species). We have found that the mean Hamming distance 12 to 16 weeks after the onset of acute infection predicts whether the patient will recover from HCV infection or develop persistent infection and chronic liver disease. Patients who recover have a declining Hamming distance as antibody to HCV develops, signifying immunologic containment and then clearance of the virus. In contrast, the majority of patients demonstrate an increased mean hamming distance as antibody appears. This suggests that if the immune response is not sufficient to clear the virus, it paradoxically exerts immune pressure that results in mutations (escape variants) that lead to persistent infection. Interestingly, patients with fulminant hepatitis have a very low degree of viral diversity because they succumb to the infection before the immune system can clear the virus or exert immune pressure. This study has been published on Science in 2000(The outcome of acute hepatitis C predicted by the evolution of the viral quasi-species; Science 288:339-344).In ongoing studies, we are measuring the viral quasi-species throughout the long-term course of HCV infection and the relation of the quasispecies other parameters to the outcome of HCV infection. Thus far, studies have shown that patients with chronic HCV infection have impaired CD4 and CD8 cell responses to all HCV antigens compared to patients who recover from acute HCV infection.We have also found that neutralizing antibodies do not correlate with recovery from acute HCV infection, but rather continue to increase in strength and breath of activity over the course of chronic infection. Despite these antibodies, escape mutants continue to evade the immune response. Most recently, we have compared patients who have severe, rapidly progressive hepatitis C to those who have a stable indolent course. We found that patients with rapid progression have a delayed or impaired immunologic response to HCV, an inability to reduice viral load early in infection, a greater degree of viral diversity, a diminished interferon response and, importantly, an early and sustained elevation of the pro-fibrogenic cytokine, MCP-1. We are now testing in a larger cohort wheteher MCP-1 could serve as a predictive marker of severe fibrosis in patients with chronic hepatitis C. Ongoing studies are looking for other cytokines or micro RNAs that might predict fibrosis progression. In this regard we have shown that the miRNA, Let-7, is a predictive marker of fibrosis progression.